Aspirin has been in use for over 100 years. The mechanism of action of this common drug was not fully appreciated until 1971 when it was discovered that the ability of aspirin to suppress inflammation lies primarily in its ability to inhibit the cyclooxygenase (COX) enzyme. Subsequently, two cyclooxygenase isoforms have been identified, designated as COX-1 and COX-2. The COX enzymes catalyze conversion of arachidonic acid to prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2); (see FIG. 1). PGH2 is then converted to a variety of prostaglandins and other eicosanoids that play a role in inflammation and other disease processes. Aspirin inhibits the action of COX-1 and COX-2 and thereby reduces prostaglandin and other eicosanoid levels and acts as an anti-inflammatory agent.
Prostaglandins (PG) are oxygenated fatty acids that bind to G-protein coupled receptors (GPCRs). Several naturally occurring prostaglandins, PGD2, PGE2, PGF2α, and PGI2, have been identified. Prostaglandins produce numerous physiologic and pathophysiologic effects and regulate cellular processes in nearly every tissue. The wide spectrum of prostaglandin action includes effects on immune, endocrine, cardiovascular, renal and reproductive systems as well as the contraction and relaxation of smooth muscle. Accordingly, drugs that effect prostaglandin production such as aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) have been used to prevent or alleviate a variety of conditions including, for example, cardiovascular disease, discomfort associated with minor injuries and headaches, and of severe pain caused by a variety of inflammatory and degenerative joint diseases.
Given the broad role of prostaglandins in normal human physiology, it is not surprising that systemic suppression of prostaglandin synthesis through inhibition of the COX enzymes can lead to unwanted side effects. In particular, individuals taking NSAIDs for even short periods of time can experience gastrointestinal and renal side effects, in addition to effects on other physiological systems. As many as 25% of individuals using NSAIDs experience some type of side effect, and as many as 5% develop serous health consequences such as gastric bleeding, ulceration, or perforation.
While COX-1 and COX-2 carry out essentially the same catalytic reaction and have similar primary protein structures, the expression patterns of these isoforms are distinct. In general, COX-1 is expressed constitutively in nearly all normal tissues, while COX-2 is expressed at low to undetectable levels in normal tissues but is induced in certain circumstances such as in response to injury or inflammation. Recently, drugs that selectively inhibit COX-2 (coxibs) have been proposed as a safer alternative to traditional NSAIDs. Although some of these selective inhibitors of COX-2 have demonstrated better gastrointestinal safety compared to traditional non-selective NSAIDs, questions remain regarding their effects on renal and cardiovascular systems. In addition, selective inhibitors of COX-2 do not appear to have the protective cardiovascular effect observed with traditional NSAIDs such as aspirin.
A goal of clinical pharmacology and the pharmaceutical industry is the development of more selective drugs with greater efficacy and fewer side effects than those currently in use. In order to more effectively treat conditions where COX-1 modulators can be of benefit, such as inflamation and cardiovascular disease, COX-1 modulatory drugs with greater selectivity must be discovered. New COX-1 variants, such as alternatively spliced COX-1 polypeptides, can be more closely associated with a disease such as cardiovascular disease than the known COX-1 isoform and, thus, can be novel targets for drug discovery efforts, resulting in the discovery of drugs with greater efficacy or fewer side effects than drugs developed against the known COX-1 isoform.
Thus, there exists a need for the discovery of new COX-1 variants which can be used, for example, to design more specific drugs with fewer side effects. The present invention satisfies this need and provides related advantages as well.